HDL in Children with CKD Promotes Endothelial Dysfunction and an Abnormal Vascular Phenotype

Endothelial dysfunction begins in early CKD and contributes to cardiovascular mortality. HDL is considered antiatherogenic, but may have adverse vascular effects in cardiovascular disease, diabetes, and inflammatory conditions. The effect of renal failure on HDL properties is unknown. We studied the endothelial effects of HDL isolated from 82 children with CKD stages 2–5 (HDL^CKD), who were free of underlying inflammatory diseases, diabetes, or active infections. Compared with HDL from healthy children, HDL^CKD strongly inhibited nitric oxide production, promoted superoxide production, and increased vascular cell adhesion molecule-1 expression in human aortic endothelial cells, and reduced cholesterol efflux from macrophages. The effects on endothelial cells correlated with CKD grade, with the most profound changes induced by HDL from patients on dialysis, and partial recovery observed with HDL isolated after kidney transplantation. Furthermore, the in vitro effects on endothelial cells associated with increased aortic pulse wave velocity, carotid intima-media thickness, and circulating markers of endothelial dysfunction in patients. Symmetric dimethylarginine levels were increased in serum and fractions of HDL from children with CKD. In a longitudinal follow-up of eight children undergoing kidney transplantation, HDL-induced production of endothelial nitric oxide, superoxide, and vascular cell adhesion molecule-1 in vitro improved significantly at 3 months after transplantation, but did not reach normal levels. These results suggest that in children with CKD without concomitant disease affecting HDL function, HDL dysfunction begins in early CKD, progressing as renal function declines, and is partially reversed after kidney transplantation.Patients with CKD no longer die from renal failure but from cardiovascular disease. There is an independent, graded association between a reduced eGFR and the risk of death and cardiovascular events.¹ Typically, patients with CKD develop calcification in the tunica media of their arteries,² but a concomitant process of endothelial damage leading to atherosclerosis is also³ present beginning in predialysis CKD.^4,5LDL is crucially involved in the pathogenesis of atherosclerotic cardiovascular disease in the general population,⁶ whereas HDL is thought to be antiatherogenic by promoting reverse cholesterol transport and exerting direct protective endothelial effects.⁷ HDL from healthy participants increases the bioavailability of nitric oxide (NO) by activating endothelial NO synthase inducing vasodilation and decreasing arterial BP. Moreover, HDL diminishes the production of reactive oxygen species such as superoxide (SO) radicals, which have been demonstrated to reduce NO bioavailability leading to endothelial dysfunction and promoting atherogenesis. However, recent evidence suggests that HDL may lose its vasoprotective properties in patients with manifest cardiovascular disease (e.g., coronary artery disease), diabetes, or inflammatory disease states (e.g., antiphospholipid syndrome).^8–10 Similarly, in adults on dialysis, HDL has reduced cholesterol efflux capacity and proinflammatory effects on mononuclear cells.^11–13 Observational studies have shown a strong association between high HDL levels and reduced risk of cardiovascular disease in the general population¹⁴ but not in dialysis patients.¹⁵Cardiac and vascular damage has also been documented in children on dialysis,^2,16,17 and cardiovascular disease accounts for the majority of deaths in pediatric dialysis patients.¹⁷ In contrast with adult patients with CKD, in whom cardiovascular risk factors such as diabetes dyslipidemia, hypertension, and smoking are highly prevalent,¹⁸ CKD in children is mainly caused by inherited disorders such as malformations of the kidney or urinary tract.¹⁸ Accordingly, examining HDL function in children who are free of “traditional” cardiovascular risk factors and underlying inflammatory diseases and who are nonsmokers gives us an unique opportunity to study the effects of renal failure on the vascular functions of HDL.We studied the endothelial properties of HDL in a cohort of children at different stages of CKD on dialysis and after transplantation and compared them with healthy children. Furthermore, to determine the clinical relevance of in vitro effects of HDL, we examined its relationship with clinical measures of the vascular phenotype as well as circulating markers of endothelial dysfunction. Finally, to show a causal link between renal function and HDL properties, we examined children on dialysis and 3 months after kidney transplantation. This study allowed us to examine when HDL dysfunction develops during the natural history of renal decline, its effects on vascular function, and the potential for recovery after kidney transplantation.     

Comprehensive review of the impact of direct oral anticoagulants on thrombophilia diagnostic tests: Practical recommendations for the laboratory

There is a laboratory and clinical need to know the impact of direct oral anticoagulants (DOACs) on diagnostic tests to avoid misinterpretation of results. Although the regulatory labelling documents provide some information about the influences of each DOAC on diagnostic tests, these are usually limited to some of the most common tests and no head to head comparison is available. In this paper, we report the impact of DOACs on several thrombophilia tests, including assessment of antithrombin, protein S and protein C activity assays, detection of activated protein C resistance and assays used for lupus anticoagulant. Results are compared and discussed with data obtained from literature. The final goal of this comprehensive review is to provide practical recommendations for laboratories to avoid misdiagnosis due to oral direct factor Xa (FXa) or IIa (FIIa) inhibitors. Overall, oral direct FXa (apixaban, betrixaban, edoxaban and rivaroxaban) and FIIa (dabigatran) antagonists may affect clot-based thrombophilia diagnostic tests resulting in false-positive or false-negative results. An effect on FIIa-based thrombophilia diagnostic tests is observed with dabigatran but not with anti-FXa DOACs and conversely for FXa-based thrombophilia diagnostic tests. No impact was observed with antigenic/chromogenic methods for the assessment of protein S and C activity. In conclusion, interpretation of thrombophilia diagnostic tests results should be done with caution in patients on DOACs. The use of a device/chemical compound able to remove or antagonize the effect of DOACs or the development of new diagnostic tests insensitive to DOACs should be considered to minimize the risk of false results.     

The HcrVf2 gene from a wild apple confers scab resistance to a transgenic cultivated variety

The Vf gene from the wild species Malus floribunda 821 is the most studied apple scab resistance gene. Several molecular markers mapping around this gene were the starting point for a positional cloning project. The analysis of the bacterial artificial chromosome clones spanning the Vf region led to the identification of a cluster of genes homologous to the Cladosporium fulvum resistance gene family of tomato. One of these genes, HcrVf2 (homologue of the C. fulvum resistance genes of the Vf region), was used to transform the susceptible apple cultivar Gala. Four independent transformed lines resistant to apple scab were produced, proving that HcrVf2 is sufficient to confer scab resistance to a susceptible cultivar. The results show that direct gene transfer between cross-compatible species can be viable when, as in apple, the use of backcrosses to introduce resistance genes from wild species cannot exactly reconstitute the heterozygous genotype of clonally propagated cultivars.     

Gender and utilization of ancillary services

OBJECTIVE: To determine whether gender is associated with the use of ancillary services in hospitalized patients. DESIGN: A retrospective study of laboratory and radiology tests ordered for medical and surgical inpatients over 16-month and 20-month periods, respectively. Obstetric patients were excluded. MEASUREMENTS AND MAIN RESULTS: Number of clinical laboratory and radiology tests per admission, their associated charges, and total charges per admission were measured. In crude analyses, women had 16.5% fewer clinical laboratory tests (p < .0001) with 18.8% lower associated charges (p < .0001) and 24.4% fewer radiology tests (p < .0001) with 15.6% lower associated charges (p < .0001) than men. Total changes for the admission were lower for women in both the clinical laboratory study period ($16,178 vs $18,912, p < .0001) and the radiology study period ($14,621 vs $18,182, p < .0001). When adjusted for age, race, insurance status, service, diagnosis-related-group weight, and length of stay, these differences were smaller but persisted: women had 3.7% fewer laboratory tests performed (p < .001) with 4.8% lower associated charges (p < .001). In similarly adjusted analyses for radiology studies, women received 10.4% fewer radiology examinations (p < .001), with 4.1% lower associated charges (p < .01). There were no significant differences in the adjusted total charges in the laboratory group ($17,450 vs $17,655, p=.20) and only a marginally significant difference in the radiology group ($16,278 vs $16,498, p = .05). When we compared ancillary utilization within the five largest diagnosis-related groups, these differences persisted. CONCLUSIONS: Men receive more ancillary services than women, even after adjusting for potential confounders. This study was supported by research grant R01-HS07107-01 from the Agency for Health Care Policy and Research. Dr. Jha was supported in part by the Carl W. Walter fund of Harvard Medical School.     

Memory from the dynamics of intrinsic membrane currents

Almost all theoretical and experimental studies of the mechanisms underlying learning and memory focus on synaptic efficacy and make the implicit assumption that changes in synaptic efficacy are both necessary and sufficient to account for learning and memory. However, network dynamics depends on the complex interaction between intrinsic membrane properties and synaptic strengths and time courses. Furthermore, neuronal activity itself modifies not only synaptic efficacy but also the intrinsic membrane properties of neurons. This paper presents examples demonstrating that neurons with complex temporal dynamics can provide short-term “memory” mechanisms that rely solely on intrinsic neuronal properties. Additionally, we discuss the potential role that activity may play in long-term modification of intrinsic neuronal properties. While not replacing synaptic plasticity as a powerful learning mechanism, these examples suggest that memory in networks results from an ongoing interplay between changes in synaptic efficacy and intrinsic membrane properties.     

Overtreatment and Deintensification of Diabetic Therapy among Medicare Beneficiaries

Background

Deintensification of diabetic therapy is often clinically appropriate for older adults, because the benefit of aggressive diabetes treatment declines with age, while the risks increase.

Objective

We examined rates of overtreatment and deintensification of therapy for older adults with diabetes, and whether these rates differed by medical, demographic, and socioeconomic characteristics.

Design, Subjects, and Main Measures

We analyzed Medicare claims data from 10 states, linked to outpatient laboratory values to identify patients potentially overtreated for diabetes (HbA1c < 6.5% with fills for any diabetes medications beyond metformin, 1/1/2011–6/30/2011). We examined characteristics associated with deintensification for potentially overtreated diabetic patients. We used multinomial logistic regression to examine whether patient characteristics associated with overtreatment of diabetes differed from those associated with undertreatment (i.e. HbA1c > 9.0%).

Key Results

Of 78,792 Medicare recipients with diabetes, 8560 (10.9%) were potentially overtreated. Overtreatment of diabetes was more common among those who were over 75 years of age and enrolled in Medicaid (p < 0.001), and was less common among Hispanics (p = 0.009). Therapy was deintensified for 14% of overtreated diabetics. Appropriate deintensification of diabetic therapy was more common for patients with six or more chronic conditions, more outpatient visits, or living in urban areas; deintensification was less common for those over age 75. Only 6.9% of Medicare recipients with diabetes were potentially undertreated. Variables associated with overtreatment of diabetes differed from those associated with undertreatment.

Conclusions

Medicare recipients are more frequently overtreated than undertreated for diabetes. Medicare recipients who are overtreated for diabetes rarely have their regimens deintensified.

     

Effects of cyclooxygenase and lipoxygenase inhibition on eicosanoids and healing of acetic acid colitis in rats

Both cyclooxygenase products, such as prostaglandin (PG) E₂, and lipoxygenase products, such as leukotriene (LT) B₄, are increased in colitis and have potent proinflammatory actions. We studied effects of specific inhibitors of cyclooxygenase and 5-lipoxygenase on the healing of acetic acid colitis in rats. Acetic acid colitis was induced 24 hr before enzyme inhibition began. Four days after induction of colitis, the area of gross colonic mucosal damage was determined by image analysis. Eicosanoid content in the intestinal lumen was quantitated by radioimmunoassay following chromatographic purification. Under these conditions, indomethacin significantly retarded the healing of colonic lesions and inhibited PGE₂ by >90% compared to placebo-treated colitis rats. AA861 had no effect on the healing of lesions, although >75% inhibition of leukotriene synthesis was demonstrated. These results suggest that inhibition of endogenous colonic prostaglandins can impair healing mechanisms in acute colitis even after inflammation has developed. In contrast, inhibition of leukotriene synthesis did not affect healing.     

18F-FDG PET/CT in bone sarcoidosis: an observational study

Clinical Rheumatology - Bone sarcoidosis is usually rare. Imaging procedures such as fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) can reveal bone...